TREM1/DAP12 based novel multiple chain CAR-T cells targeting DLL3 show robust anti-tumour efficacy for small cell lung cancer.

Small cell lung cancer (SCLC), recognized as the most aggressive subtype of lung cancer, presents an extremely poor prognosis. Currently, patients with small cell lung cancer face a significant dearth of effective alternative treatment options once they experience recurrence and progression after first-line therapy. Despite the promising efficacy of immunotherapy, particularly immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) and various other tumours, its impact on significantly enhancing the prognosis of SCLC patients remains elusive. DLL3 has emerged as a compelling target for targeted therapy in SCLC due to its high expression on the membranes of SCLC and other neuroendocrine carcinoma cells, with minimal to no expression in normal cells. Our previous work led to the development of a novel multiple chain chimeric antigen receptor (CAR) leveraging the TREM1 receptor and DAP12, which efficiently activated T cells and conferred potent cell cytotoxicity. In this study, we have developed a DLL3-TREM1/DAP12 CAR-T (DLL3-DT CAR-T) therapy, demonstrating comparable anti-tumour efficacy against SCLC cells in vitro. In murine xenograft and patient-derived xenograft models, DLL3-DT CAR-T cells exhibited a more robust tumour eradication efficiency than second-generation DLL3-BBZ CAR-T cells. Furthermore, we observed elevated memory phenotypes, induced durable responses, and activation under antigen-presenting cells in DLL3-DT CAR-T cells. Collectively, these findings suggest that DLL3-DT CAR-T cells may offer a novel and potentially effective therapeutic strategy for treating DLL3-expressing SCLC and other solid tumours.

Advances in the Diagnosis and Treatment of Advanced Non-Small-Cell Lung Cancer With EGFR Exon 20 Insertion Mutation.

The discovery of epidermal growth factor receptor (EGFR) mutations has greatly changed the clinical outlook for patients with advanced non-small-cell lung cancer (NSCLC). Unlike the most common EGFR mutations, such as exon 19 deletion (del19) and exon 21 L858R point mutation, EGFR exon 20 insertion mutation (EGFR ex20ins) is a rare mutation of EGFR. Due to its structural specificity, it exhibits primary resistance to traditional epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), leading to poor overall survival prognosis for patients. In recent years, there has been continuous progress in the development of new drugs targeting EGFR ex20ins, bringing new hope for the treatment of this patient population. In this regard, we conducted a systematic review of the molecular characteristics, diagnostic advances, and treatment status of EGFR ex20ins. We summarized the latest data on relevant drug development and clinical research, aiming to provide reference for clinical diagnosis, treatment, and drug development.

Effects of methionine deficiency on B7H3-DAP12-CAR-T cells in the treatment of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LUSC) is a subtype of lung cancer for which precision therapy is lacking. Chimeric antigen receptor T-cells (CAR-T) have the potential to eliminate cancer cells by targeting specific antigens. However, the tumor microenvironment (TME), characterized by abnormal metabolism could inhibit CAR-T function. Therefore, the aim of this study was to improve CAR-T efficacy in solid TME by investigating the effects of amino acid metabolism. We found that B7H3 was highly expressed in LUSC and developed DAP12-CAR-T targeting B7H3 based on our previous findings. When co-cultured with B7H3-overexpressing LUSC cells, B7H3-DAP12-CAR-T showed significant cell killing effects and released cytokines including IFN-γ and IL-2. However, LUSC cells consumed methionine (Met) in a competitive manner to induce a Met deficiency. CAR-T showed suppressed cell killing capacity, reduced cytokine release and less central memory T phenotype in medium with lower Met, while the exhaustion markers were up-regulated. Furthermore, the gene NKG7, responsible for T cell cytotoxicity, was downregulated in CAR-T cells at low Met concentration due to a decrease in m5C modification. NKG7 overexpression could partially restore the cytotoxicity of CAR-T in low Met. In addition, the anti-tumor efficacy of CAR-T was significantly enhanced when co-cultured with SLC7A5 knockdown LUSC cells at low Met concentration. In conclusion, B7H3 is a prospective target for LUSC, and B7H3-DAP12-CAR-T cells are promising for LUSC treatment. Maintaining Met levels in CAR-T may help overcome TME suppression and improve its clinical application potential.

Almonertinib plus chemotherapy versus almonertinib alone in second-line treatment of advanced non-small cell lung cancer with mutated epidermal growth factor receptor: a retrospective study.

Objective: This study mainly observes the efficacy and safety of almonertinib plus chemotherapy compared with almonertinib alone in the second-line treatment of advanced non-small cell lung cancer (NSCLC) with mutated epidermal growth factor receptor (EGFR). Methods: In this study, clinical data of 68 patients with advanced NSCLC who were treated in Jiangsu Provincial People's Hospital and Nanjing Chest Hospital between April 2020 and December 2022 were collected. Among them, the study group (n=30) received second-line almonertinib combined with platinum-based chemotherapy, while the control group (n=38) received almonertinib alone. The near-term and long-term effects and adverse events of the two groups were compared respectively. Results: The median follow-up time until 31 December 2022 was 16.3 months (95% CI: 11.32-21.34). Results of chi-square analysis showed no statistically significant difference in objective response rate (ORR) and disease control rate (DCR) between the study group and the control group (56.73% vs. 55.3%, P>0.05; 100% vs. 86.8%, P>0.05). Log-rank test comparing the two groups revealed that the median progression-free survival (mPFS) of the study group was significantly longer than that of the control group by 3.1 months (12.7 vs. 9.6 months, P=0.01). Multivariate COX proportional risk model showed a statistically significant effect of treatment method and PS score on PFS (HR=0.43, P=0.023; HR=3.82, P=0.001). In terms of safety, most of the adverse events (AEs) were mild, with no grade 4-5 in the two groups, and the overall tolerance of patients was good. Conclusion: For advanced NSCLC patients with EGFR mutations, second-line treatment with almonertinib plus chemotherapy significantly improved PFS compared with almonertinib alone without a significant increase in adverse events, providing efficacy and safety.

THOC3 interacts with YBX1 to promote lung squamous cell carcinoma progression through PFKFB4 mRNA modification.

The THO complex (THOC) is ubiquitously involved in RNA modification and various THOC proteins have been reported to regulate tumor development. However, the role of THOC3 in lung cancer remains unknown. In this study, we identified that THOC3 was highly expressed in lung squamous cell carcinoma (LUSC) and negatively associated with prognosis. THOC3 knockdown inhibited LUSC cell growth, migration, and glycolysis. THOC3 expression was regulated by TRiC proteins, such as CCT8 and CCT6A, which supported protein folding. Furthermore, THOC3 could form a complex with YBX1 to promote PFKFB4 transcription. THOC3 was responsible for exporting PFKFB4 mRNA to the cytoplasm, while YBX1 ensured the stability of PFKFB4 mRNA by recognizing m5C sites in its 3'UTR. Downregulation of PFKFB4 suppressed the biological activities of LUSC. Collectively, these findings suggest that THOC3, folded by CCT proteins can collaborate with YBX1 to maintain PFKFB4 expression and facilitate LUSC development. Therefore, THOC3 could be considered as a novel promising therapeutic target for LUSC.

RB1 aberrations predict outcomes of immune checkpoint inhibitor combination therapy in NSCLC.

Introduction: Immune checkpoint inhibitors (ICI) have changed the treatment of non-small cell lung cancer (NSCLC). Furthermore, compared with monotherapy, ICI combination therapy had better efficacy and partly different mechanism. Therefore, we aim to investigate and improve biomarkers specialized for ICI combination therapy. Methods: We enrolled 53 NSCLC patients treated with ICI combination therapy and collected their tissue and plasma samples to perform next-generation sequencing (NGS) with a 425-gene panel. Results: The line of treatment was the only clinical factor significantly affecting objective response rate (ORR) and progression-free survival (PFS). Surprisingly, classical markers PD-L1 and TMB only had limited predictive values in the ICI combination therapy. Instead, we found RB1 mutation was significantly associated with prognosis. Patients with mutated RB1 had shorter PFS than those with wild RB1 (134d vs 219d, p=0.018). Subsequent analysis showed the RB1 related mutated cell cycle and chromosomal instability were also deleterious to prognosis (103d vs 411d, p<0.001; 138d vs 505d, p=0.018). Additionally, patients with more circulating tumor DNA (ctDNA) had significantly shorter PFS (41d vs 194d, p=0.0043). Conclusion: This study identified that NSCLC patients with mutated RB1 were less sensitive to ICI combination therapy. RB1 mutations and following cell cycle abnormalities and chromosomal instability can potentially guide clinical management.

Afatinib for the Treatment of NSCLC with Uncommon EGFR Mutations: A Narrative Review.

Afatinib, the world's first irreversible ErbB family (containing four different cancer cell epidermal growth factor receptors, including EGFR, HER2, ErbB3, and ErbB4) inhibitor, is a second-generation oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It can be used as a first-line treatment for locally advanced or metastatic non-small-cell lung cancer (NSCLC) with an EGFR-sensitive mutation or for patients with locally advanced or metastatic squamous lung cancer whose disease progresses during or after platinum-containing chemotherapy. Currently, with the use of third-generation EGFR-TKIs, afatinib is no longer clinically indicated as the first choice for patients with NSCLC who have EGFR-sensitive mutations. However, afatinib showed a considerable inhibitory effect in NSCLC patients with uncommon EGFR mutations (G719X, S768I, and L861Q) according to a combined post hoc analysis of the LUX-Lung2/3/6 trials. With the development of genetic testing technology, the detection rate of uncommon EGFR mutations is increasing. The aim of this paper is to describe in detail the sensitivity of rare EGFR mutations to afatinib and to provide information and a reference for those suffering from advanced NSCLC who have uncommon EGFR mutations.

Real world experience with camrelizumab in patients with advanced non-small cell lung cancer: a prospective multicenter cohort study (NOAH-LC-101).

Background: Camrelizumab has shown promising survival benefits in treatment-naïve advanced non-small cell lung cancer (NSCLC) patients when used in combination with chemotherapy. However, its effectiveness and safety outside the clinical trial setting are largely unknown. Therefore, we conducted NOAH-LC-101, a prospective multicenter cohort study, to investigate the real-world effectiveness and safety of camrelizumab on a large cohort of advanced NSCLC patients in daily clinical practice. Methods: All consecutive patients aged ≥18 years with confirmed advanced NSCLC scheduled for camrelizumab treatment were screened for inclusion at 43 hospitals in China. The primary outcome was progression-free survival (PFS). The secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Between August 2019 and February 2021, 403 patients were included. The median age of participants was 65 years (range, 27-87 years). There were 57 (14.1%) participants with an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≥2. Most participants received camrelizumab in the second or later lines (68.7%) and plus chemotherapy (64.8%). The median PFS was 12.6 [95% confidence interval (CI): 10.7-17.0] months and median OS was 22.3 months [95% CI: 19.3-not reached (NR)]. The ORR was 28.8% (95% CI: 24.4-33.5%) and DCR was 79.9% (95% CI: 75.7-83.7%). Adverse events of any grade occurred in 348 (86.4%) participants. No new safety signals were identified. Reactive cutaneous capillary endothelial proliferation was observed in 75 (18.6%) patients, all of which were grade 1-2. Conclusions: This study demonstrates the effectiveness and safety of camrelizumab in a large sample of real-world NSCLC patients. The results are generally consistent with those previously reported in pivotal clinical trials. This study supports the clinical use of camrelizumab in a broader patient population (ChiCTR1900026089).

Investigation of the Wind-Direction Effect on Buoyancy-Driven Fire Smoke Dispersion in an Urban Street Canyon.

When a fire occurs in a street canyon, smoke recirculation is the most harmful factor to human beings inside the canyon, while the wind condition is an essential factor determining if the smoke is recirculated. This paper focuses on the wind direction's effect on buoyancy-driven fire smoke dispersion in a street canyon, which is innovative research since the effect of wind direction has not been reported before. In this study, an ideal street canyon model with a height-width ratio of 1 was established, and both the wind velocity and wind direction were changed to search for the critical point at which smoke recirculation occurs. The results show that with an increase in the wind direction angle (the angle of wind towards the direction of the street width), the smoke recirculation could be distinguished into three regimes, i.e., the "fully re-circulation stage", the "semi re-circulation stage", and the "non-recirculation stage". The critical recirculation velocity was increased with the increase in the wind direction angle, and new models regarding the critical wind velocity and the Froude number were proposed for different wind direction conditions.

Circulating tumor DNA detection in MRD assessment and diagnosis and treatment of non-small cell lung cancer.

Circulating tumor DNA (ctDNA) has contributed immensely to the management of hematologic malignancy and is now considered a valuable detection tool for solid tumors. ctDNA can reflect the real-time tumor burden and be utilized for analyzing specific cancer mutations via liquid biopsy which is a non-invasive procedure that can be used with a relatively high frequency. Thus, many clinicians use ctDNA to assess minimal residual disease (MRD) and it serves as a prognostic and predictive biomarker for cancer therapy, especially for non-small cell lung cancer (NSCLC). Advanced methods have been developed to detect ctDNA, and recent clinical trials have shown the rationality and feasibility of ctDNA for identifying mutations and guiding treatments in NSCLC. Here, we have reviewed recently developed ctDNA detection methods and the importance of sequence analyses of ctDNA in NSCLC.

Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the leading cause of cancer-related death. Despite advances in chemotherapy and immunotherapy, the prognosis for advanced patients remains poor. The discovery of oncogenic driver mutations, such as anaplastic lymphoma kinase (ALK) mutations, means that a subset of patients has opportunities for targeted therapy. With the improvement of genetic testing coverage, more and more ALK fusion subtypes and ALK partners have been discovered, and more than 90 rare ALK fusion subtypes have been found in NSCLC. However, unlike the common fusion, echinoderm microtubule-associated protein-like 4 (EML4)-ALK, some rare ALK fusions such as striatin (STRN)-ALK and huntingtin interacting protein 1 (HIP1)-ALK, etc., the large-scale clinical data related to its efficacy are still immature. The clinical application of ALK-tyrosine kinase inhibitors (ALK-TKIs) mainly depends on the positivity of the ALK gene, regardless of the molecular characteristics of the fusion partner. Recent clinical studies in the ALK-positive NSCLC population have demonstrated differences in progression-free survival (PFS) among patients based on different ALK fusion subtypes. This article will introduce the biological characteristics of ALK fusion kinase and common detection methods of ALK fusion and focus on summarizing the differential responses of several rare ALK fusions to ALK-TKIs, and propose corresponding treatment strategies, so as to better guide the application of ALK-TKIs in rare ALK fusion population.

Comprehensive Molecular Analyses of an SLC Family-Based Model in Stomach Adenocarcinoma.

Background: Solute carrier (SLC) family members are crucial in transporting amino acids across membranes. Amino acids are indispensable for both cancer and immune cells. However, the clinical significance of amino acid transporting SLC members in stomach adenocarcinoma (STAD) remains unclear. This study aimed to develop an SLC family-based model to predict the prognosis and the response of STAD patients to immunotherapy. Methods: A total of 1239 tumor cases were obtained from online databases. The training set (n = 371) consisted of RNA sequencing profiles obtained from The Cancer Genome Atlas (TCGA), while those from Gene Expression Omnibus (GEO) were used as the test set. Subsequently, the clinical characteristics and immune profiles were investigated, and potential immunotherapy response prediction values of the model were assessed. Results: Based on the TCGA cohort, an SLC family-based model was developed using multivariate Cox analysis. All tumor cases were stratified into high- and low-risk groups considering the SLC model. High-risk patients had a worse overall survival (OS) than low-risk patients, consistent with the results of GEO cohorts. Comprehensive analyses revealed that the high-risk group was correlated with aggressiveness-related pathways, whereas the low-risk group had better T helper cell infiltration and stronger immunotherapy response. Compared to the high-risk group, the low-risk group presented increased PD-L1 and tumor mutation burden. Conclusion: This SLC family-based model has the potential to predict the prognosis and immunotherapy outcomes of STAD patients. The survival of patients in the low-risk group was greatly prolonged, and the patients may benefit more from immunotherapy.

Revolution of CAR Engineering For Next-Generation Immunotherapy In Solid Tumors.

Chimeric antigen receptor (CAR)-T cells have enormous potentials for clinical therapies. The CAR-T therapy has been approved for treating hematological malignancies. However, their application is limited in solid tumors owing to antigen loss and mutation, physical barriers, and an immunosuppressive tumor microenvironment. To overcome the challenges of CAR-T, increasing efforts are put into developing CAR-T to expand its applied ranges. Varied receptors are utilized for recognizing tumor-associated antigens and relieving immunosuppression. Emerging co-stimulatory signaling is employed for CAR-T activation. Furthermore, other immune cells such as NK cells and macrophages have manifested potential for delivering CAR. Hence, we collected and summarized the last advancements of CAR engineering from three aspects, namely, the ectodomains, endogenous domains, and immune cells, aiming to inspire the design of next-generation adoptive immunotherapy for treating solid tumors.

Numerical Simulation of the Smoke Recirculation Behavior in Street Canyons with Different Aspect Ratios and Cross-Wind Conditions.

This study investigated smoke dispersion inside a street canyon in a series of numerical simulations. The building height and street width as well as the cross-wind velocity were changed during the simulation, and the smoke recirculation behavior inside the canyon is presented and discussed. The results show that the smoke recirculation behavior could be distinguished into two different stages, i.e., the "fully recirculation stage" and "semi recirculation stage", which is strongly determined by the canyon aspect ratio (the building height divided by street width). It was found that the critical wind velocity at which the smoke recirculation would take place was almost constant for an ideal street canyon with an aspect ratio of 1; however, this velocity was decreased with increasing building height or decreasing street width, indicating a much more dangerous circumstance when the aspect ratio is greater. Finally, a new piecewise function is proposed for the critical smoke recirculation velocity for all cases, which can provide some theoretical basis for building designs and emergency rescue for human beings inside the street canyon.

Adebrelimab or placebo plus carboplatin and etoposide as first-line treatment for extensive-stage small-cell lung cancer (CAPSTONE-1): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is associated with poor prognosis and treatment options are scarce. Immunotherapy has shown robust clinical activity in ES-SCLC in previous phase 3 trials. We aimed to assess the efficacy and safety of adebrelimab (SHR-1316), a novel anti-PD-L1 antibody, with standard chemotherapy as a first-line treatment for ES-SCLC. METHODS: The CAPSTONE-1 study was a randomised, double-blind, placebo-controlled, phase 3 trial, done in 47 tertiary hospitals in China. Key inclusion criteria were patients aged 18-75 years, with previously untreated histologically or cytologically confirmed ES-SCLC and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Eligible patients were randomly assigned (1:1) to receive four to six cycles of carboplatin (area under the curve of 5 mg/mL per min, day 1 of each cycle) and etoposide (100 mg/m2 of body-surface area, on days 1-3 of each cycle) with either adebrelimab (20 mg/kg, day 1 of each cycle) or matching placebo, followed by maintenance therapy with adebrelimab or placebo. All treatments were given intravenously in 21-day cycles. Randomisation was done using a centralised interactive web response system with a block size of four, stratified by liver metastases, brain metastases, and lactate dehydrogenase concentration. The primary endpoint was overall survival in patients who received at least one dose of study medication. Safety was analysed in the as-treated population. This study is complete and registered with ClinicalTrials.gov, NCT03711305. FINDINGS: Between Dec 26, 2018, and Sept 4, 2020, 462 eligible patients were enrolled and randomly assigned: 230 (50%) patients received adebrelimab plus chemotherapy (adebrelimab group) and 232 (50%) patients received placebo plus chemotherapy (placebo group). At data cutoff (Oct 8, 2021), median follow-up was 13·5 months (IQR 8·9-20·1). Median overall survival was significantly improved in the adebrelimab group (median 15·3 months [95% CI 13·2-17·5]) compared with the placebo group (12·8 months [11·3-13·7]; hazard ratio 0·72 [95% CI 0·58-0·90]; one-sided p=0·0017). The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (174 [76%] patients in the adebrelimab group and 175 [75%] patients in the placebo group), decreased white blood cell count (106 [46%] and 88 [38%]), decreased platelet count (88 [38%] and 78 [34%]), and anaemia (64 [28%] and 66 [28%]). Treatment-related serious adverse events occurred in 89 (39%) patients in the adebrelimab group and 66 (28%) patients in the placebo group. Four treatment-related deaths were reported: two each in the adebrelimab group (respiratory failure and interstitial lung disease and pneumonia) and placebo group (multiple organ dysfunction and unknown cause of death). INTERPRETATION: Adding adebrelimab to chemotherapy significantly improved overall survival with an acceptable safety profile in patients with ES-SCLC, supporting this combination as a new first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Effects of heating rate on thermal degradation behavior and kinetics of representative thermoplastic wastes.

Waste thermoplastics are the most common solid wastes, and thermal degradation has excellent advantages in the disposal of these wastes and obtaining valuable hydrocarbon fuels. As a significant factor, the heating rate is crucial to the thermal degradation process. Consequently, thermal degradation behavior and kinetics of representative thermoplastics under different heating rates were investigated by using thermogravimetric analysis and differential scanning calorimetry in the air. Kinetic parameters were estimated by using the Coats-Redfern method. Subsequently, the Shuffled Complex Evolution (SCE) method was used to optimize kinetic parameters, and the optimized results were compared with the calculated kinetics of distributed activation energy model (DAEM) method to find the effects of heating rate on kinetic parameters. The results showed that with the increase of heating rate, thermogravimetric curves moved to the right, which corresponded to a higher temperature range. The number of mass loss rate peaks and exothermic peaks decreased. Additionally, activation energy was the same at the determined minimum and maximum heating rates, and other heating rates had little effect on kinetic parameters. Moreover, the calculated activation energy of the DAEM method at the minimum heating rate of 5 K/min was closest to the optimized values of the SCE method, indicating that the lower the minimum heating rate was, the more accurate the activation energy was.

Pyrolysis and combustion characteristics of typical waste thermal insulation materials.

Thermal insulation materials are important for building energy conservation, but their wastes have increased sharply. Furthermore, pyrolysis and combustion are increasingly utilized to dispose of solid wastes and convert them into value-added fuels. To better understand the pyrolysis and combustion characteristics of these materials, typical thermal insulation materials (expanded polystyrene (EPS) and extruded polystyrene (XPS)) were investigated by employing thermogravimetry and differential scanning calorimetry as well as cone calorimetry experiments. Pyrolysis behavior, kinetic parameters, pyrolysis index, thermodynamic parameters, endothermic properties and combustion parameters were estimated comprehensively. The results showed that EPS had better pyrolysis properties, while XPS had better combustion characteristics. Activation energies of EPS and XPS were 158.82 kJ/mol and 200.70 kJ/mol, respectively. Additionally, EPS had a higher pyrolysis stability index and comprehensive pyrolysis index, meaning a more intense reaction. Moreover, thermodynamic parameters indicated that the devolatilization products could be obtained easily from the two materials, and EPS and XPS could be converted into fuels. For the combustion, XPS had a smaller fire performance index and a larger fire growth index. These results can guide the reactor design and optimization for better converting polymer wastes into fuels and managing wastes.

LINC01001 Promotes Progression of Crizotinib-Resistant NSCLC by Modulating IGF2BP2/MYC Axis.

Background: Crizotinib is a microtubule-related protein-4-anaplastic lymphoma kinase (EML4-ALK) multi-target tyrosine kinase inhibitor applied in the treatment of ALK-rearranged NSCLC. However, the specific molecular mechanism underlying its therapeutic effect remains unclear. Therefore, the purpose of this research is to explore the mechanism by which crizotinib targets NSCLC with ALK-rearrangement, mainly whether it is related to LINC01001 in regulating NSCLC progression via IGF2BP2/MYC axis. Methods: RT-qPCR is conducted to evaluate the mRNA levels of LINC01001, IGF2BP2 and MYC in A549/R and H1299/R cells. CCK-8 and EdU assays are performed to assess the viability and proliferation of A549/R and H1299/R cells. Western blot is conducted to measure the levels of PCNA and Ki-67 proteins in A549/R and H1299/R cells. FACs and TUNEL are performed to detect apoptosis of A549/R and H1299/R cells. Immunohistochemical staining is performed to assess the levels of Ki67 in crizotinib-resistant NSCLC tissue. Bioinformatics analysis of multiple CLIP (crosslinking-immunoprecipitation) data found potential binding sites between LINC01001 and IGF2BP2, IGF2BP2 and MYC, that are confirmed by RIP assay and RNA pulldown assay. Results: Our findings illustrated that LINC01001 is highly expressed in crizotinib-resistant NSCLC cells and associated with poor overall survival of NSCLC patients. Inhibition of LINC01001 depresses crizotinib resistance of NSCLC cells. LINC01001 interacts with IGF2BP2, and inhibition of IGF2BP2 depresses crizotinib resistance of NSCLC cells. IGF2BP2 interacts with the mRNA of MYC, and LINC01001 overexpression increases crizotinib resistance of NSCLC via MYC. Conclusion: LINC01001 promotes the progression of crizotinib-resistant NSCLC by modulating the IGF2BP2/MYC axis. Our research clarifies the specific mechanism of crizotinib-resistance in NSCLC treatment.

Novel two-chain structure utilizing KIRS2/DAP12 domain improves the safety and efficacy of CAR-T cells in adults with r/r B-ALL.

Engineered T cells that express chimeric antigen receptors (CARs) have been a promising therapy for hematologic malignancies. The optimization of CAR structure using different signaling domains can alter a wide range of CAR-T cell properties, including anti-tumor activity, long-term persistence, and safety. In this study, we developed a novel CAR structure based on KIRS2/Dap12 for B cell acute lymphoblastic leukemia (B-ALL) antigen CD19 and compared the anti-tumor efficacy and safety of this construct in transduced T cells with standard second-generation CAR-T cells targeting CD19 for B-ALL in vitro and in vivo and in adult relapsed/refractory (r/r) B-ALL patients. We discovered that KIRS2/Dap12 receptor infused with 4-1BB co-stimulation domain could enhance anti-tumor efficacy by remarkably increasing the production of pro-inflammatory interleukin-2 (IL-2), especially when co-cultured with antigen-positive tumor cells. In addition, CD19-KIRS2/Dap12-BB CAR-T cells showed the inspiring outcome that complete responses were seen in 4 of 4 (100%) patients without neurotoxicity and a high rate of severe cytokine release syndrome (CRS) after CAR-T infusion in a phase I clinical trial. Given these encouraging findings, CD19-KIRS2/Dap12-BB CAR-T cells are safe and can lead to clinical responses in adult patients with r/r B-ALL, indicating that further assessment of this therapy is warranted.

A Comprehensive Investigation on the Fire Hazards and Environmental Risks in a Commercial Complex Based on Fault Tree Analysis and the Analytic Hierarchy Process.

This paper focuses on the fire risk assessment for commercial complex, as the variety of fire accidental triggers inside could be a big threat to the public fire safety, leading to catastrophic loss in human lives and properties. Both the qualitative and quantitative analysis were imposed on a typical large commercial complex to recognize the potential fire-causative factors in this paper. Applying the fault tree analysis, the basic events leading to fire are acquired, and they are then further reclassified based on the analytic hierarchy process. Taking the damage of the accident as the target layer and the fire-causative factors, the equipment operation factors and firefighting factors as the criterion layer, the assessment index is well established. The risk of each factor is quantitatively evaluated, and the effect of each factor on the target layer is analyzed. The result of the fault tree analysis and analytic hierarchy process shows good consistency, in which human behavior is the main factor leading to the fire occurrence, followed by the combustible material, the rescue speed and the staff assignment factors. The results are beneficial for general decisions and measures in public fire safety management.